Telomerase-based therapy for retarding immune exhaustion

R.B. Effros
University of California, Los Angeles, Los Angeles, CA

Reduced function of T lymphocytes has been implicated in the age-associated increased morbidity and mortality due to infections as well as in the enhanced risk of cancer. Like other normal human cells, T lymphocytes are limited in their proliferative potential. Cell culture studies of repeatedly stimulated T cells have identified a variety of phenotypic, genetic and functional changes associated with the end stage of replicative senescence. Increased proportions of T cells with similar features accumulate with age in humans and are part of a cluster of immune parameters that predict early mortality in a group of eighty-year olds.

Our research has shown that gene therapy with the catalytic component of human telomerase not only stabilizes telomere length, but also retards the loss of immune control over viral infections. More recent studies have shown that similar effects can be mediated by a small molecule telomerase activator, TAT2. Exposure of T cells to TAT2 leads to increased proliferative potential, enhanced production of anti-viral cytokines, and augmented anti-viral cytotoxicity. The enhanced anti-viral effects were abrogated in the presence of a potent and specific telomerase inhibitor, suggesting that TAT2 acts primarily through telomerase activation. Our studies indicate that telomerase activators, such as TAT2, may constitute a novel class of therapeutic agents for treatment of a variety of age-related diseases associated with immune deficiency that require enhanced proliferation and function of T lymphocytes. (Supported by NIH, Geron Corporation and TA Therapeutics, Ltd.)